The long-term goal of this project is to understand the neurobiology of Alzheimer's disease (AD), and to identify potential novel therapies for AD. Various forms of AB cause synaptic dysfunction, result in degeneration of axons and dendrites, induce neuronal death and decrease adult neurogenesis in animal models of AD. Recent data raise the possibility that Neuregulin-I (NRG1), or manipulation of NRG1 signaling, could provide several beneficial effects in candidate neuropathologic substrates of AD. We will test the hypothesis that NRG1 and its interplay with physical activity will ameliorate AD-related cognitive decline in mice by reducing AB load, promoting neuroprotection and stimulating neurogenesis. Through differential splicing of the NRG1 transcript and stepwise proteolytic processing, several subtypes of NRG1 are generated. Type I NRG1 has been shown to down-regulate levels of APP mRNA and protein in C2C12 cells. Our preliminary data indicate that exogenous type 111 NRG1 decreases amyloid deposition in APPtg mice. Expression of neprilysin, a key AB-degrading enzyme, is increased in the brain of mice following injection of lentiviruses expressing type 111 NRG1. Expression of NRG1 and erbB receptors in the dentate gyrus (DG) is markedly increased by exercise and neural activity in young animals; physical and neural activities promote adult neurogenesis. Our preliminary results also indicate that expression of NRG1 is reduced in aged brains and is increased following physical exercise. It has recently been reported that adult neurogenesis in the DG is significantly decreased in heterozygote type 111 NRG1 mutants, and our preliminary results show that overexpression of NRG1 increases adult neurogenesis in young adult mice. Collectively, these data indicate that understanding the role of NRG1 signaling in AD animal models may lead to novel concepts of AD pathogenesis or treatment. Aim 1 is to determine whether NRG1 signaling reduces AB load and ameliorates neuropathology in an APPtg mouse model of AD. Aim 2 is to determine mechanisms by which NRG1 signaling regulates AB load. Aim 3 is to determine whether an interaction between NRG1 signaling and physical activity affects neuronal structure, neurogenesis and cognitive function in APPtg mice.